ABSTRACT
The in silico construction of a PDGFRß kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted in significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.
ABSTRACT
The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.
Subject(s)
Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Mice , Molecular Structure , Oximes/chemistry , Pyrazoles/chemistryABSTRACT
The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Amino Acid Substitution , Animals , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Humans , Indazoles/chemistry , Mice , Microsomes, Liver/metabolism , Mutation , Oximes/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf.
Subject(s)
Indans/chemistry , Oximes/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyridines/chemistry , Animals , Binding Sites , Cell Line, Tumor , Computer Simulation , Drug Evaluation, Preclinical , Humans , Indans/chemical synthesis , Indans/pharmacokinetics , Microsomes, Liver/metabolism , Models, Chemical , Models, Molecular , Oximes/chemical synthesis , Oximes/pharmacokinetics , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies.
